The present Phase 2 SBIR application builds on the previous Phase 1 SBIR award to identify a markedly improved biguanide to replace metformin in the treatment of T2D. Over 135 new biguanides were synthesized in the Phase 1 work and analyzed for their ability to produce metformin-like activity in cells and animal models but at a much lower effective concentration. The findings show that the aims of the Phase 1 research were met by the generation of promising candidates that are more effective than metformin. In the work proposed, a limited number of new biguanides will be synthesized, based on the structure-function relationships identified in the Phase 1 work. These and the other novel biguanides in the NovaTarg library will be tested in cell and animal models of diabetes to understand their potential to treat this disease. A preclinical candidate will be selected and advanced to GLP safety studies. The results of this work will position the novel biguanide for an IND to treat T2D. The reason for conducting this drug discovery work lies in the inability of current drugs to treat T2D and control the disease. Unfortunately, more than 1/3 of affected individuals fail to achieve healthy blood glucose levels. Of the therapies used, metformin (i.e. Glucophage, a member of the biguanide drug class) is the most prominent of the drugs as measured by the number of prescriptions issued worldwide. Unfortunately, up to 10% of potential patients cannot tolerate this agent because of gastrointestinal adverse effects while another, even larger, segment of the diabetic population with renal insufficiency cannot take metformin because of the risk of lactic acidosis, a life-threatening condition generated by a decrease in metformin elimination by the kidney. In the current application, the preclinical candidate for an IND will be chosen for its ability to act on liver, fat and skeletal muscle throug the OCT family of transporters and be excluded from the kidney. Overall, the agent should provide for better efficacy and less side-effects. Moreover, the selection of this candidate will involve its ability to inhibit cancer cell proliferation, an effect not optimized for metformin. T2 has an increased risk for cancer development and our preclinical biguanide should protect against this feature of the disease better than any other drug category. We believe that this is a unique aspect of our drug discovery program along with the increase in efficacy to lower blood glucose and reduce the side-effects found with metformin. Overall, we expect that a much larger % of the T2D population will be able to use our drug and the efficacy on glucose control and on anti-cancer effects will be much greater than that found for metformin.